An Improved, Scalable and Cost Effective One-Pot Synthesis of ...

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
____________________________________________Research Article
An Improved, Scalable and Cost Effective One-Pot Synthesis of
Telmisartan
Premchand B. Patil 1* , Anand Pandey 1 , Devanand B. Shinde 2 and Bhata R. Chaudhari 1*
1
Organic Research Laboratory Department of Chemistry, JET’s Z. B. PatilCollege,
Dhule, Maharashtra, India.
2
Department of Chemical Technology Dr. BabasahebAmbedkarMarathwadaUniversity,
Aurangabad, Maharashtra, India.
__________________________________________________________________________________
ABSTRACT
An efficient and environmentally benign synthesis, cost-effective and improved one-potsynthesis for
telmisartan1 is described that reduced the number of operations and gives high-purity.
Keywords: One-pot synthesis, antihypertensive,telmisartan.
INTRODUCTION
Telmisartan is of Synthetic origin. It belongs to
Angiotensin-II receptor antagonist 1
pharmacological group on the basis of mechanism
of action and also classified in antihypertensive
agents pharmacological group.Angiotensin II
receptor antagonist used in the administration of
hypertension, heart strokes and bladder diseases 2-
3 .Telmisartan is an angiotensin II receptor blocker
which shows high affinity for the angiotensin II
receptor type 1 (AT 1 ). It has largest volume of
distribution. In addition to blocking the reninangiotensin
system (RAS), telmisartan acts as a
selective modulator of peroxisome proliferatoractivated
receptor gamma (PPAR-γ), a central
regulator of insulin and glucose metabolism. It is
believed that telmisartan dual mode of action may
provide protective benefits against the vascular and
renal damage caused by diabetes and
cardiovascular disease (CVD). 4 It’s chemical name
is 4'-((1,4'-dimethyl-2'-propyl(2,6'-bi-1H-
benzimidazole)-1'-yl)methyl)-1,1'-biphenyl-2-
carboxylic acid, which is represented by Fig. 1.
N
CH 3
N
CH 3
1
N
N
CH 3
Fig. 1: Structure of Telmisartan
COOH
The various reported synthetic routes for the
manufacturing of telmisartan 5-11 . The general
reaction consists of condensation of 2-n-propyl-4-
methyl-6-(1′-methylbenzimidazol-2′-
yl)benzimidazole 2 with 4'-(bromomethyl)
biphenyl-2-carbonitrile or alkyl ester of 4'-
bromomethyl biphenyl3 in presence of organic
solvents and base to form 4'-((1,4'-dimethyl-2'-
propyl(2,6'-bi-1h-benzimidazole)-1'-yl)methyl)-
1,1'-biphenyl-2-carbonitrile or alkyl ester 4and
further hydrolyzed with strong base at 25 - 200°C
by using various solvents to produce the
telmisartan hydrochloride or telmisartan1(Scheme
1).
The above synthetic route process is good but there
is furthermore scope for development of this
process to avoid number of purification
processes,number of operations such as excess use
of various solvents andalso workup at high
temperature, filtration, drying and ash content is
major issue which affects on its poor yield and
purity.Therefore this process is difficult to
commercialise.
Synthesis for the telmisartan using of 4’-
bromomethyl-biphenyl-2-carboxylic acid alkyl
ester 12 has also been reported.Synthesis of 4’-
bromomethyl-biphenyl-2-carboxylic acid alkyl
ester having disadvantages such as a poor stability
hence could not store longer period. Therefore, it
was always used freshly prepared. During the
synthesis it was decomposed at high temperature
and gives side product, which is impact on quality
and low yield. Formation of dibromo impurity
during synthesis of 4’-bromomethyl-biphenyl-2-
carboxylicacid alkyl ester in bromination. Hence
this is not suitable for the industrial production
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International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
because poor working efficiency, high cost and
safety.
The novel one-pot synthesis for telmisartan which
mainly focused on the improved yield and high
level of purity without further purification process
and thus meeting all the regulatory norms as
follows:
In this process 4'-(bromomethyl) biphenyl-2-
carbonitrile3used which is cheap cost andhas more
stability as compare to 4’-bromomethyl-biphenyl-
2-carboxylic acid alkyl ester and thus it helps
toimprove the yield and purity,which impact on the
cost of process. It also reduced the ash content,
avoiding further purification process anddoes not
required special operation. Herein, we report an
efficient cost effective and scalable process suitable
for the industrial production to improve the
purity,yield and safety.
N
CH 3 Br CH3
CH3
N
N
N
N
Base
CH 3
N
CH
N 3
N
Base
H N
N
CH 3 R
N
CH
N
3
CH 3 R
CH 3
COOH
2
3
4
1
R= Nitrile or Methyl ester or
Tert. butyl ester.
R= Nitrile or Methyl ester or
Tert. butyl ester
Schem
e 1:Reported synthetic scheme of telmisartan
N
CH3
N
CH 3
N
H
N
CH 3
Br
CN
Aceton/KOH
CH 3
N
N
N
N
CH 3
CH 3
CN
Ethylene glycol/KOH
MeOH
CH 3
N
N
N
N
CH 3
CH 3
COOH
2 3 5 1
Scheme 2:Improved synthetic scheme of telmisartan
EXPERIMENTAL
Preparation of 4’-[4-methyl-6-(1-methyl-1H-
benzimidazol-2-yl)-2-propyl-1H-benzimidazol-
1ylmithyl]-2-carboxylic acid
80ml of acetone, 10 gm of2-n-propyl-4-methyl-6-
(1′-methyl benzimidazol-2′-yl) benzimidazole2 and
2.2 gm of potassium hydroxide is added into four
neck RB flask. Stir reaction for one hour at 25 to
35°C. Add 9.0gm of 4’-(bromomethyl) biphenyl-2-
carbonitrile 3. Reaction mass is stirred at 25 to
35°C for 1 – 3hrs. Reaction is monitored by TLC,
after completion of reaction acetone is distilled out
under vacuum at 35-40°C. Add 70ml of ethylene
glycol, 10gm of potassium hydroxide. The reaction
mixture is stirred at 100-105°C for 15hrs to 20hrs.
Reaction is monitored by TLC. After completion of
reaction mixture is cooled to 30-35°C. Add 100ml
of methanol. Telmisartan1 is precipitated out by
adding 25ml of acetic acid then add 60ml of DM
water. Filter the solid and followed by wash with
aq. methanol. The wet material dissolved in 70ml
of methanol in 1.6gm of potassium hydroxide.
After treatment of charcoal crystallize the
telmisartan1 by adding acetic acid at pH 5.8 to 6.3.
Then finished product was filtered out and washed
with DM water. Finally dry the material under
vacuum at 60°C to give pure telmisartan1. [Yield
87%, Purity 99.97% by HPLC.M.P. 260 – 262°C,
Sulphated ash < 0.01%].
1 H NMR (DMSO-d6): δ 0.98-1.03 (t,3H), 1.73-
1.86 (m, 2H), 2.5 - 2.63 (s, 3H), 2.90-2.95 (s,
2H),3.82 (s, 3H), 5.62 (s, 2H), 7.16-7.34 (m,7H),
7.40-7.59 (m,4H), 7.68-7.70 (m, 3H), 12.86 (s,
1H). M/Z: 515.50 [M + H] +
RESULT AND DISCUSSION
We have developed cost-effective and improved
one-pot synthesis for telmisartan which described
in scheme 2. For the preparation of 4'-((1,4'-
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International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
dimethyl-2'-propyl(2,6'-bi-1h-benzimidazole)-1'-
yl)methyl)-1,1'-biphenyl-2-carbonitrile. We have
selected 4’-(bromomethyl) biphenyl-2-carbonitrile
3 key raw material because it is very cheapest and
commercially easily available in the market.
Condensation of 2-n-propyl-4-methyl-6-(1′-
methylbenzimidazol-2′-yl) benzimidazole 2 with
4'-(bromomethyl) biphenyl-2-carbonitrile 3 in
acetone using potassium hydroxide as a base to
give 4'-((1,4'-dimethyl-2'-propyl(2,6'-bi-1h-
benzimidazole)-1'-yl)methyl)-1,1'-biphenyl-2-
carbonitrile 5, in situ which was hydrolysed by
using potassium hydroxide in ethylene glycol to
give potassium salt of telmisartan 1. It is isolated
by acetic acid to give pure telmisartan1 in good
yield and high purity. Telmisartan 1 obtained by
using this process consistently has less than 0.1%
sulphated ash.
The major ratio of compound 3 used for
condensation of compound 2 to obtained
compound 4 is less than other processes and it is
reduced to 1.0 equivalent to obtained compound 5.
After combination of both steps (i.e. condensation
and hydrolysis) compound 1 is obtained. The
product obtained has various advantages such as
good yield, avoiding purification, commercial
scalable with easier handling, greater efficiency,
high purity and lower cost.
CONCLUSION
We have provided an improved and industrially
feasible manufacturing one-pot process for
telmisartan 1 which is free from impurities and
meets the pharmacopeial norms. The present onepot
synthesis scale up process allowed us to
prepare pure telmisartan with more than 99% purity
with more than 85% overall yield.
ACKNOWLEDGEMENT
The Authors are thankful to the Management,
Principal and Head, Dept. of Chemistry, JET’s Z.B.
Patil College Dhule, for providing the lab facilities
and constant encouragement.
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